The purpose of this project is to determine the organization of the neurotransmitter systems involved in the control of cholinergic neurons projecting from the septum to the cortex, hippocampus and interpeduncular nucleus of the rat. The turnover rate of acetylcholine, which will be determined by a gas chromatographic-mass spectrometric method, will be used as an index of activity of the cholinergic neurons. The neurotransmitter systems involved and their action on the cholinergic neurons will be identified by determining the turnover rate of acetylcholine after the administration of psychopharmacological agents either systemically or directly into discrete areas of the brain, after lesioning specific neuronal pathways, and after electrical stimulation of specific neuronal pathways. To be studied are: (1) noradrenergic pathways originating in the locus coeruleus and in other brainstem cell groups, (2) serotonergic pathways from the dorsal and median raphe nuclei, (3) enkephalin-containing neurons in the septum, amygdala, and other areas, and (4) their interaction with each other as well as with dopaminergic neurons and GABAergic interneurons in the septum in the control of cholinergic neurons. Also to be studied is the ability of agents such as antipsychotic, antidepressant, and opiate compounds to return to normal values, and changes in activity of cholinergic neurons caused by lesions of specific neurotransmitter systems. The extent of lesion will be determined by measuring the level of neurotransmitter involved in specific brain areas. Activity of noradrenergic systems after electrical stimulation will be indicated by the level of 3-methoxy-4-hydroxyphenylglycol (MHPG) and of serotonergic systems by 5-hydroxyindoleacetic acid (5-HIAA). Dopamine and norepinephrine content will be determined by high performance liquid chromatography with amperometric detection. MHPG and serotonin and its metabolite 5-HIAA will be determined spectrofluorometrically. Enkephalin will be measured by radioimmunoassay.